Modern drug discovery has been revolutionized by the development of high-throughput screening techniques. The ability to clone receptors, combined with modern automation techniques, means that now thousands of compounds can be screened for receptor binding and, by extension, pharmaceutical activity, in the time previously required to screen only a few. Hodgson, 10 Biotech. 973 (1992). Because of this screening capacity, new compound generation is now often the rate-limiting step in drug discovery. Dewitt, 1 Pharm. News 11 (1994). In addition, the statistics of this screening approach to drug discovery requires the testing of many thousands of compounds in order to discover one highly active new compound. The traditional sources of compounds for screening, such as natural products or the products of rational drug design, cannot furnish the numbers of compounds needed to meet this demand, while combinatorial synthesis produces large numbers of compounds but they have insufficient diversity of structures. The present invention is directed at the development of a new method to synthesize and screen large numbers of structurally diverse compounds.
There are two principal ways in which candidate compounds are currently provided for drug screening: isolation from natural products, and chemical synthesis. Natural products, such as plant extracts, provide a great amount of structural diversity. However, this approach typically requires laborious sample collection and preparation, followed by difficulties in identification, isolation, and production of compounds determined to be active via screening. Consequently, this approach is typically too slow to meet the capacity offered by high-throughput screening. Traditional chemical synthesis is also slow, and new technologies--primarily combinatorial approaches to stepwise synthesis--are being developed to rapidly generate collections of molecules for drug discovery. Dewitt, Ibid. Such combinatorial approaches can provide sufficient quantities of compounds quickly enough for high-throughput screening, but the structural diversity is restricted due to the limited number of starting materials and synthetic reactions for combining starting materials.
Plasma glow discharges have been used to prepare specific compounds from vaporized organic reactants. See, for example, Cvetanovic, 1 Adv. Photochem. 115 (1963) wherein the production of an aldhyde, two epoxides and two ketones from a mixture of 2-pentene and oxygen was reported. See also, Suhr, 11 Angew. Chem. Int. Ed. Engl. 781 (1972), which discloses the limited production of several cyclic compounds from acetylene; however, unless the reaction is rapidly quenched, the primary products are polymers. Ibid. The primary focus of prior attempts to synthesize new products by exposure of one or more reactants to a glow discharge has been to maximize conversion and yield of a single desired product which, due to the inherent difficulty in controlling plasma discharge reactions, has been largely unsuccessful. The present invention is based upon the recognition that such inherent uncontrollability can be used to advantage in preparing a multitude of organic compounds containing diverse chemical structures and functional groups, and that the resultant product mix, when coupled with bioactivity screening, can ultimately lead to the production of significant numbers of useful compounds.